The present invention relates to a novel N-substituted-Nxe2x80x2-substituted urea derivative, a pharmaceutical composition containing the same, a TNF-xcex1 production inhibitory agent and a therapeutic agent for treating an autoimmune disease.
TNF-xcex1 (Tumor Necrosis Factor-xcex1) has presently been recognized as a cytokine strongly correlated with biological protection-immunological mechanism, but the continuous and excess production of TNF-xcex1 causes various tissue disorders and this accordingly becomes a principal cause of a variety of diseases and exacerbation. For instance, examples of pathogenesis associated with TNF-xcex1 include articular rheumatism, systemic erythematodes (SLE), dyscrasia, acute infectious diseases, allergy, fever, anemia and diabetes (YAMAZAKI, Clinical Immunology, 1995, 27:1270). Moreover, it has also been reported that TNF-xcex1 plays an important role in the crisis of chronic rheumatism and Crohn""s disease, which are autoimmune diseases (Andreas Eigler et al., Immunology Today, 1997, 18:487).
Accordingly, a compound capable of inhibiting the production of TNF-xcex1 or controlling the action thereof would be effective in the treatment of the foregoing diseases and therefore, a variety of investigations have been done to obtain such a compound (the foregoing articles: YAMAZAKI, Clinical Immunology, 27; Andreas Eigler et al., Immunology Today, 18).
An object of the present invention is to provide a novel compound having an activity of inhibiting TNF-xcex1 production.
It is another object of the present invention to provide an intermediate useful in the preparation of the foregoing compound.
It is a further object of the present invention to provide a pharmaceutical composition containing the foregoing compound, a TNF-xcex1 production inhibitory agent and a therapeutic agent for treating autoimmune diseases.
The inventors of this invention have conducted intensive studies to synthesize a compound having a urea structure as a basic structure, which has not conventionally been investigated as a drug, have established a large number of novel compounds, have found that N-substituted-Nxe2x80x2-substituted urea derivatives represented by the following general formula I among the foregoing novel compounds show an excellent TNF-xcex1 production inhibitory activity and thus have completed the present invention on the basis of the foregoing finding.
More specifically, the present invention herein provides an N-substituted-Nxe2x80x2-substituted urea derivative represented by the following general formula I as well as a pharmaceutically acceptable salt thereof: 
wherein R1 represents a hydrogen atom, a lower alkyl group, an aryl group or a group represented by the following general formula II: 
wherein R2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a carboxyl group or an ester group, or R2 may form a ring together with R1; R3 and R4 may be the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group, an adamantylalkyl group, an arylalkyl group, a cycloalkyl group or an aryl group; R5 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group or an aryl group; R6 and R7 may be the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group, a cycloalkyl group or an aryl group; A1 and A2 may be the same or different and each represents a lower alkylene group, provided that R5 and either R6 or R7 together or R6 and R7 together form a 5- to 7-membered ring and that either of the substituents R3 and R4 represents a cycloalkylalkyl group, an adamantylalkyl group or an arylalkyl group.
According to the present invention, there are also provided N-substituted-Nxe2x80x2-substituted urea derivatives represented by the following general formula III as well as salts thereof: 
The present invention likewise provides a pharmaceutical composition, a TNF-xcex1 production inhibitory agent and a therapeutic agent for treating autoimmune diseases, which comprise the foregoing N-substituted-Nxe2x80x2-substituted urea derivative or a pharmaceutically acceptable salt thereof.
In the present invention, the lower alkyl group may be, for instance, linear or branched alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl and isohexyl groups, with alkyl groups having 1 to 6 being preferred. The lower alkyl group is more preferably those having 1 to 3 carbon atoms, in particular, methyl group. Examples of cycloalkyl groups are those having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, with those having 3 to 6 carbon atoms being preferred and cyclohexyl group being particularly preferred. Examples of lower alkoxy groups include linear or branched alkoxy groups having 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and hexyloxy groups, with those having 1 to 5 carbon atoms being preferred and those having 1 to 3 carbon atoms being particularly preferred.
These lower alkyl, cycloalkyl and lower alkoxy groups may be substituted wiTNFor instance, halogen atoms (such as fluorine, chlorine, iodine and bromine atoms) and/or a hydroxyl group. Moreover, the cycloalkyl group may be substituted with a lower alkyl group and/or a lower alkoxy group.
Examples of lower alkylene groups are linear or branched alkylene groups having 1 to 8 carbon atoms such as methylene, ethylene, propylene, isopropylene, methylmethylene, tetramethylene, 2-methyltrimethylene and hexamethylene groups, with those having 1 to 5 carbon atoms being preferred. The lower alkylene group is more preferably those having 2 to 4 carbon atoms and in particular, those having 2 to 3 carbon atoms.
In addition, examples of aryl groups are phenyl groups, naphthyl groups and aromatic heterocyclic groups having 6 to 12 carbon atoms, which may be substituted or unsubstituted and the aryl group is preferably a substituted or unsubstituted phenyl group and particularly preferably an unsubstituted phenyl group or a biphenylyl group. In this respect, the substituent may be, for instance, a halogen atom (such as fluorine, chlorine, iodine or bromine atom), a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, a cycloalkyl group or a phenyl group.
Examples of cycloalkylalkyl, adamantylalkyl and arylalkyl groups are linear or branched alkyl groups having 1 to 8 carbon atoms, preferably alkyl groups having 1 to 5 carbon atoms, more preferably alkyl groups having 1 to 3 carbon atoms and most preferably ethyl group, to which the foregoing cycloalkyl, adamantly or aryl group is bonded.
Examples of ester groups are lower alkyl esters, benzyl esters and phenyl esters.
Examples of rings formed by the combination of substituents R2 and R1 are 5- and 6-membered non-aromatic hetero rings including the sulfur atom to which R1 is bonded as a member of the rings, such as tetrahydrothiophene, thiolactone and dithiolan.
Examples of 5- to 7-membered rings formed by the combination of R6 with R6 or R7 or the combination of R6 and R7 are non-aromatic hetero rings having a nitrogen atom or a combination of a nitrogen atom and an oxygen or sulfur atom in the ring, with those having one or two nitrogen atoms and those having a nitrogen atom and an oxygen atom being more preferred. Specific examples thereof include pyrroline, pyrrolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine; piperidine, piperazine, morpholine, homo-piperazine and homo-piperidine rings. Among these rings, preferred are pyrroline, pyrrolidine, tetrahydropyridine, piperidine, piperazine, morpholine and homo-piperidine rings, with pyrrolidine, piperidine, piperazine, tetrahydropyridine and homo-piperidine rings being more preferred. Particularly preferably used herein are pyrrolidine, piperidine and homo-piperidine rings. These 5- to 7-membered rings may be substituted wiTNFor instance, lower alkyl groups, lower alkylamino groups, amino groups and/or hydroxyl group or may be condensed with a benzene ring.
When the compound represented by the general formula I according to the present invention has thiol, hydroxyl, amino and/or nitrogen atom-containing hetero ring, these groups may be protected with commonly used protective groups.
Examples of protective groups for thiol group are those commonly used as protective groups for thiol group such as acyl groups and substituted thio groups. Specific examples thereof are acyl groups such as lower alkanoyl groups, phenylcarbonyl groups, thenoyl groups, nicotinoyl groups, lower alkoxycarbonyl groups, substituted lower alkoxycarbonyl groups and substituted carbamoyl groups; and substituted thio groups such as lower alkylthio groups and phenylthio group. In this connection, the phenyl rings of the foregoing phenylcarbonyl and phenylthio groups may be substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group.
Among these, preferred are, for instance, acyl groups such as acetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group, thenoyl group, t-butoxycarbonyl group and benzyloxycarbonyl group; and substituted thio groups such as ethylthio, t-butylthio and phenylthio groups, with lower alkylcarbonyl groups (in particular, those having 2 to 5 carbon atoms) being more preferably used.
Protective groups for hydroxyl group may be, for instance, those commonly used as the protective groups for hydroxyl group such as acyl groups, substituted lower alkyl groups and substituted silyl groups. Specific examples thereof are acyl groups such as formyl group, lower alkanoyl groups, halogenated lower alkanoyl groups, phenylcarbonyl groups, lower alkoxycarbonyl groups and phenyl lower alkoxycarbonyl groups; substituted lower alkyl groups such as allyl group, lower alkoxy lower alkyl groups, substituted lower alkoxy lower alkyl groups, phenyl lower alkyl groups, tetrahydropyranyl groups and tetrahydrofuranyl groups; and substituted silyl groups such as lower alkyl silyl groups and phenyl silyl group. In this respect, the phenyl rings of the foregoing phenylcarbonyl, phenyl lower alkoxycarbonyl, phenyl lower alkyl and phenyl silyl groups may be substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group.
Among these, preferably used as such protective groups are acyl groups such as formyl, acetyl, pivaloyl, monochloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl and benzyloxy- carbonyl groups; substituted alkyl groups such as allyl, methoxymethyl, 1-ethoxyethyl, 2-methoxyethoxymethyl, benzyloxymethyl, benzyl, 4-methoxybenzyl, trityl, 2-tetra- hydropyranyl and 2-tetrahydrofuranyl groups; and substituted silyl groups such as trimethyl silyl, triethyl silyl, triisopropyl silyl, t-butyldimethyl silyl and t-butyldiphenyl silyl groups, with tri(lower alkyl) silyl groups being more preferred.
Examples of protective groups for amino and nitrogen atom as a member of a hetero ring are those commonly used as protective groups for amino and nitrogen atom as a member of a hetero ring such as acyl groups, substituted lower alkyl groups and substituted sulfonyl groups. Specific examples thereof are acyl groups such as formyl, lower alkanoyl, halogenated lower alkanoyl, phenylcarbonyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl and phenoxycarbonyl groups; substituted lower alkyl groups such as allyl, phenyl lower alkyl and benzoyl lower alkyl groups; and substituted sulfonyl groups such as lower alkylsulfonyl and phenylsulfonyl groups. In this connection, the phenyl rings of the foregoing phenylcarbonyl, phenoxycarbonyl, phenyl lower alkyl, benzoyl lower alkyl and phenylsulfonyl groups may be substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group.
Among these protective groups, preferred are acyl groups such as formyl, acetyl, trichloroacetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl and phenoxycarbonyl groups; substituted alkyl groups such as allyl, benzyl, trityl and (4-methoxyphenyl) diphenylmethyl; and substituted sulfonyl groups such as benzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl and toluenesulfonyl groups, with lower alkoxycarbonyl groups being more preferred.
In the compound of Formula I according to the present invention, R1 is preferably a hydrogen atom, a lower alkyl group or a group represented by Formula II and if R1 represents a hydrogen atom, preferred compounds include those protected with thiol protective groups. Moreover, R1 is preferably a hydrogen atom or a lower alkyl group and if R1 represents a hydrogen atom, preferred compounds include those necessarily protected with thiol protective groups. In addition, if R1 is a lower alkyl group, the lower alkyl group is preferably an unsubstituted one.
The substituent R2 is preferably a hydrogen atom or an aryl group, with hydrogen atom being particularly preferred. If R2 is an aryl group, the aryl group is preferably bonded to the 2nd or 3rd carbon atom of the substituent A1, while the carbon atom of A1 bonded to the S atom is defined to be the 1st carbon atom, with the aryl group bonded to the 2nd carbon atom of the substituent A1 being more preferred.
R3 and R4 may be the same or different and each preferably represents a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group, an adamantylalkyl or an arylalkyl group. R3 is preferably a cycloalkylalkyl group, an adamantylalkyl group or an arylalkyl group, with a cycloalkylalkyl group and an adamantylalkyl group being particularly preferred. R4 is preferably a hydrogen atom, a lower alkyl group or an arylalkyl group, with a hydrogen atom being particularly preferred.
In particular, the foregoing substituents R3 and R4 are different from one another. Among these, one of them preferably represents a hydrogen atom and R4 preferably represents a hydrogen atom. The lower alkyl groups represented by the substituents R3 and R4 are preferably linear or branched alkyl groups having 4 to 8 carbon atoms.
The substituent R5 preferably represents a hydrogen atom, a lower alkyl group, a hydroxyl group or an aryl group, with a hydrogen atom, a lower alkyl group and an aryl group being more preferred. If R5 represents a hydroxyl group, it may be protected with a hydroxyl group-protecting group. If R5 represents a group other than a hydrogen atom, R5 is preferably bonded to the 1st, 2nd or 3rd carbon atom of the substituent A2, while the carbon atom of the substituent A2 bonded to the nitrogen atom constituting a urea is defined to be the 1st carbon atom. More preferably, R5 is bonded to the 1st or 2nd carbon atom of the substituent A2.
R6 and R7 may be the same or different and each preferably represents a hydrogen atom, a lower alkyl group or an aryl group, with a lower alkyl group being more preferred.
A1 and A2 may be the same or different and each preferably represents a lower alkylene group having 2 to 4 carbon atoms and, in particular, A1 is preferably a lower alkylene group having 2 or 3 carbon atoms.
In the general formula I, the 5- to 7-membered ring formed by the combination of the substituents R5 and R5 (or R7) may be those listed above, but particularly preferred are pyrrolidine and piperidine rings. Among the 5- to 7-membered ring formed from R6 and R7, preferred are those listed above.
Among the compounds of the present invention represented by Formula I, preferred are those listed below:
(i) Compounds of Formula I wherein R1 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom or an aryl group, R3 and R4 may be the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkylalkyl group, an adamantylalkyl group or an arylalkyl group, R5 is a hydrogen atom, a lower alkyl group, a hydroxyl group or an aryl group, R6 and R7 may be the same or different and each represents a hydrogen atom, a lower alkyl group or an aryl group, and A1 and A2 may be the same or different and each represents an alkylene group having 2 or 3 carbon atoms.
(ii) Compounds of Formula I wherein R6 and R7 represents hydrogen atoms or lower alkyl groups, A1 is an alkylene group having 2 carbon atoms and A2 is an alkylene group having 2 or 3 carbon atoms, in addition to the foregoing definition (i).
(iii) Compounds of Formula I wherein R3 is a cycloalkylalkyl group, an adamantylalkyl group or an arylalkyl group and R4 is a hydrogen atom, in addition to the foregoing definition (i) or (ii).
(iv) Compounds of Formula I wherein R5 is a hydrogen atom; a lower alkyl group or an aryl group, R6 and R7 form a 5- to 7-membered ring together, in addition to the foregoing definition (i) to (iii).
(v) In the foregoing definition (iv), the 5- to 7-membered ring formed from R6 and R7 may further comprise a nitrogen, oxygen or sulfur atom, or may comprise a double bond.
(vi) In the foregoing definition (i) to (iii), R5 and R6 or R7 form a 5- to 7-membered ring and R6 or R7, which is not involved in the formation of a ring, is a lower alkyl group.
(vii) In the foregoing definition (i) to (vi), if R1 is a hydrogen atom, it is protected with a lower alkylcarbonyl group.
Specific examples of preferred compounds of the present invention are at least one member selected from the group consisting of 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-3-[2-(1-pyrrolidinyl) ethyl] urea, 1-[2-(acetylthio) ethyl-1-(2cyclohexylethyl)-3-[3-(1-pyrrolidinyl) propyl] urea, 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-3-[3-(1-piperidyl) propyl] urea, 1-[2-(acetylthio) ethyl]-3-[(1S)-1-benzyl-2-(4-methylpiperazin-1-yl) ethyl]-1-phenethyl urea, 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-xe2x80x943-[2-(1-homopiperidyl) ethyl] urea, 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-3-[2-(1,2,5,6-tetrahydropyridin-1-yl) ethyl] urea, 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-3-[[(2RS)-1-ethyl-2-pyrrolidinyl] methyl] urea, 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-3-[2-(1-piperidyl) ethyl] urea, 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-3-[2-[4-(dimethylamino)-1-piperidyl]ethyl] urea, 1-[2-(acetylthio) ethyl]-1-(2-cyclohexylethyl)-3-[(1-methyl-4-piperidyl) methyl) urea and 1-(2-cyclohexyl-ethyl)-1-[2-(methylthio) ethyl]-3-[2-(1-piperidyl) ethyl] urea, as well as pharmaceutically acceptable salts thereof.
The salts used in the present invention are not restricted to any particular one inasmuch as they are pharmaceutically acceptable salts and examples thereof are salts with inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, salts with organic acids such as acetic acid, fumaric acid, maleic acid, tartaric acid and citric acid. And salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium. In addition, the compound of the present invention may form a geometrical isomer or an optical isomer, these isomers likewise fall within the scope of the present invention. Moreover, the compound of the present invention may be in the form of a hydrate.
The compounds of the present invention represented by the general formula I may be synthesized by, for instance, the following representative. method or those similar to the same. 
The foregoing method includes the following two synthetic methods A and B.
Synthetic Method A: Compounds of Formula [IV]xe2x86x92Compounds of Formula [III]xe2x86x92Compounds of Formula I
Synthetic Method B: Compounds of Formula [IV]xe2x86x92Compounds of Formula I
These synthetic methods will be detailed below.
Synthetic Method A: 
A compound of Formula [IV] is reacted with an aminoalcohol derivative [VI] in the presence of a condensation agent (such as 1,1xe2x80x2-carbonyl diimidazole [VII]) to give a compound of Formula [III] and then the resulting compound of Formula [III] and a thio derivative [VIII] are condensed together according to the Mitsunobu reaction to give a compound represented by the general formula I according to the present invention.
Synthetic Method B: 
A compound of Formula [IV] is reacted with a compound of Formula [IX] in the presence of a condensation agent (such as 1,1xe2x80x2-carbonyl diimidazole [VII]) to directly give a compound represented by the general formula I according to the present invention. In this respect, the compound of Formula [IV] and the compound of Formula [IX] can easily be synthesized according to the method disclosed in Japanese Patent Application Ser. No. Hei 10-79154.
The compounds of the foregoing Formula [III] are novel compounds and useful intermediates for use in the preparation of the compounds represented by the general formula I according to the present invention. In the foregoing formula, R2, R3, R4, R5, R6, R7, A1 and A2 are the same as those defined above in connection with the general formula I and preferred examples thereof are likewise the same as those described above in connection with the general formula I.
In the foregoing synthetic methods, if a reactant includes a thiol, hydroxyl, amino group or a nitrogen atom as a member of a heterocyclic ring, in the molecule, these groups or atom may, if necessary, be protected with appropriate protective groups and these protective groups may be removed after the completion of the reaction according to the usual methods. In addition, if a reactant includes a carboxyl group in the molecule, the carboxyl group may, if necessary, be esterified and the ester may be converted into a carboxylic acid through hydrolysis.
In the compound of the present invention, if R2 is linked with the sulfur atom adjacent to A1 to form a thiolactone ling, the compound of the present invention can likewise be prepared according to the following method in addition to the aforementioned route. More specifically, if R2 represents a carboxyl group and R1 represents a hydrogen atom in Formula [I], the thiolactone ling may be synthesized by condensing these groups.
The compounds prepared according to the foregoing method may be converted into the corresponding salts detailed above according to the usual methods.
The TNF-xcex1 production inhibitory action of the compounds according to the present invention will be described in the following section entitled xe2x80x9cPharmacological Testsxe2x80x9d. In the tests, the inhibitory effects of the compounds on the release of TNF-xcex1 induced by the stimulation of lipopolysaccharide (LPS) were investigated in vitro and in vivo. As a result, it was found that the compounds of the present invention clearly showed an excellent TNF-xcex1 production inhibitory action.
It has been known that the productivity of TNF-xcex1 is closely related to the crisis of, for instance, autoimmune diseases such as articular rheumatism, Crohn""s disease and systemic erythematodes, dyscrasia, acute infectious diseases, allergy, fever, anemia and diabetes. Accordingly, compounds having an effect of inhibiting the production thereof such as those of the present invention would be expected to be useful as drugs for treating wide variety of these diseases.
The compound of the present invention may be administered through oral and parenteral routes. Examples of the dosage forms of the compounds include tablets, capsules, granules, powders and injections and they can be formed into these pharmaceutical preparations using techniques currently used in the art. For instance, oral drugs such as tablets, capsules, granules and powders may be prepared by, if necessary, incorporating, into the compound, a thickening agent such as lactose, crystalline cellulose, starch and vegetable oils, a lubricant such as magnesium stearate and talc, a binder such as hydroxypropyl cellulose and polyvinyl pyrrolidone, a disintegrator such as carboxymethyl cellulose, calcium and low substituted hydroxypropylmethyl cellulose, a coating agent such as hydroxypropylmethyl cellulose, macrogol and silicone resin, and a film-forming agent such as gelatin film.
The dose of the compound of the present invention may appropriately be selected depending on, for instance, the symptoms and age of each particular patient and the dosage forms, but it usually ranges from 0.1 to 5000 mg, preferably 1 to 1000 mg per day for the oral administration, which may be administered at a time or over several times in portions.
Preparation Examples of the compounds of the present invention, Examples of pharmaceutical preparations and the results of Pharmacological Tests will be given below, but they are given for deepening the understanding of the present invention and never limit the scope of the present invention at all.